The present invention relates to an improved salt form of nefazodone, an antidepressant agent. The improved salt form of this invention is a stable solid having improved dissolution characteristics throughout the gastrointestinal pH range.
Temple and Lobeck in U.S. Pat. No. 4,338,317 describe the preparation of nefazodone and analogs, their use as antidepressants, and certain acid addition salts thereof, particularly the hydrochloride salt. Specifically, Temple and Lobeck describe conversion of nefazodone and analogs to pharmaceutically acceptable acid addition salts by conventional methods. The term "pharmaceutically acceptable acid addition salts" referred to salts formed from mineral acids such as hydrochloric, hydrobromic, hydroiodic, nitric, and phosphoric acids and from organic acids such as acetic, citric, palmitic, benzoic, mandelic, mucic, isethionic, and heptanoic.
Nefazodone as the hydrochloride salt is the selected form used as the active ingredient in the prescription antidepressant product SERZONE.RTM.. Nefazodone has pk.sub.a values of about 6.4 and 9.5 and demonstrates low aqueous solubility at pH values greater than 6. Bioavailability studies directed to extended release pharmaceutical forms of nefazodone HCl suggest that the low observed bioavailability of nefazodone in extended release formulations is attributable to the low solubility of nefazodone hydrochloride in the intestinal tract where the pH ranges from about 5-7.
While aqueous solubilities differ for various salt forms of drug bases, such as nefazodone, simple aqueous solubility data by itself may be only one of several factors contributing to the bioavailability of a drug. Another factor may be the effect of pH on solubility. Where limited bioavailability is mainly due to lack of simple aqueous solubility, selection of a more water-soluble salt form can raise the drug's bioavailability. Drug solubility in aqueous solution is often a very important criterion for I.V. formulations.
Agharkar, et al. reported in the Journal of Pharm. Sci., 65/5 (May 1976), pp.747-749 that organic acid salt forms of basic drugs have higher aqueous solubilities than their corresponding halide salts. One objective of Agharkar's work was to enhance solubility of an antimalarial drug sufficiently so that parenteral administration would be feasible. At the present time Agharkar's observation is, at best, a rule of thumb as numerous exceptions to this general observation exist.
There can be several pharmaceutical strategies for enhancing drug absorption from a dosage formulation as it travels through the gastrointestinal tract. Most of these utilize special pharmaceutical formulations, with or without salt form modification, and are usually intended for use as extended release medicaments.
An example of these is described by Muhammed, et al. in U.S. Pat. No. 5,188,836 wherein a semi-enteric controlled release formulation allows absorption in both the acidic stomach environment and the neutral conditions of the small intestine. The formulation relies on use of a combination of coating materials that become soluble at different points in the digestive tract. This patent does not deal with different salt forms.
An objective of the present invention was to find a nefazodone salt that could be formulated as an extended release oral dosage form. Selection of a salt form for nefazodone that would overcome the solubility problem in the neutral environment of the small intestine is certainly not predictable beforehand. For extended release the salt should exhibit solubility under pH conditions of the small intestine as well as being bioavailable in the acidic gastric environment of the stomach. In addition, such a salt must be pharmaceutically acceptable, readily characterizable, stable under pharmaceutical processing and storage conditions, and present no special problems in handling or formulating.
There is no teaching in the prior art that would lead beforehand to selection of the methanesulfonate salt of nefazodone as a salt meeting the aforementioned criteria for incorporation into a controlled release dosage form of nefazodone.